Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

“…We suspect that avoidance of toxins (such as excessive alcohol, opioids, and inhaled anesthetic agents) and other insults (such as the hypoxia of sleep apnea, or head trauma), in addition to exercise and treatment of medical problems including hypertension or obesity may help to stabilize or slow the progression of FXTAS even in those with white matter disease as reported here ( 36 , 37 ). Perhaps supplements such as antioxidants, epicatechins or other prophylactic measures may improve mitochondrial function or white matter disease ( 38 , 39 ). Longitudinal research to uncover the risk and protective factors underlying the development and progression of FXTAS and the development of treatment targets is needed to help these vulnerable individuals with the premutation.…”

Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study

“…To this end, we utilized pharmacometabolomics [30,31] to capture the circulating metabolic signature of allopregnanolone. Furthermore, we characterized the bioenergetics of circulating lymphocytes and relate the putative improvements to cognitive and behavioral outcomes previously reported by us as a result of the open-label allopregnanolone treatment [32].…”

<p>Rapidly Progressing Neurocognitive Disorder in a Male with FXTAS and Alzheimer’s Disease</p>

“…In contrast, some areas have relatively preserved volumes and annual rate of atrophy including the corpus callosum (0.87%/year), cerebellum white matter (0.08%/year), and brainstem (1.03-1.31%/year) compared with age-matched healthy controls ( Table 2, Figure 2D-L). 18,19 The WMHs in the cerebral hemispheres and periventricular regions show several confluent areas bilaterally and significant age-related fast expansion (21.7%/year). The white matter disease also involves the right insula and the splenium of the corpus callosum, which maintains normal thickness.…”